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Mutations in PNKP cause microcephaly, seizures and defects in DNA repair

journal contribution
posted on 2023-06-07, 19:24 authored by Jun Shen, Edward C Gilmore, Christine A Marshall, Mary Haddadin, John J Reynolds, Wafaa Eyaid, Adria Bodell, Brenda Barry, Danielle Gleason, Kathryn Allen, Vijay S Ganesh, Bernard S Chang, Arthur Grix, R Sean Hill, Meral Topcu, Keith CaldecottKeith Caldecott, A James Barkovich, Christopher A Walsh
Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration(1). We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.

History

Publication status

  • Published

Journal

Nature Genetics

ISSN

1061-4036

Publisher

Nature Publishing Group

Issue

3

Volume

42

Page range

245-U38

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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